The present invention relates generally to therapeutic implants, devices, and methods useful for preventing, suppressing, or treating failure of hemodialysis vascular access grafts and other vascular procedures. The invention also relates to therapeutic implants comprising a matrix material and a therapeutic agent, wherein the composition placed in external contact with a blood vessel (perivascular implant of the composition) can be used to achieve hemostasis, e.g., to seal a breach in the vascular wall and to deliver a therapeutic agent capable of regulating the amount of tissue response to the implanted matrix.
Vascular procedures such as construction of hemodialysis access grafts and angioplasty are performed to provide vascular access in patients with renal failure in need of hemodialysis dysfunction and treat conditions such as atherosclerosis. Hemodialysis vascular access grafts can be constructed as an arterio-venous fistula (e.g., Brecisa-Cimino), or as a graft interposing either prosthetic material (e.g., polytetrafluoroethylene “PTFE”) or biological tissue (e.g., vein) between an artery and a vein.
Such grafts are usually constructed using a tubular or cylindrical segment of suitably biocompatible and substantially inert material such as PTFE, the most common material used for prosthetic dialysis access. In one approach, a segment of PTFE is surgically interposed between an artery and a vein in the arm, forearm, or thigh. The graft is then available for repeated vascular access in performing hemodialysis.
Subsequent to placement of the graft, the sutured sites in the artery and the vein undergo healing. However, 60 percent of these grafts fail, usually because of luminal narrowing, or stenosis, at the venous end. Similar lesions develop in synthetic PTFE grafts placed in the arterial circulation, although stenosis in arterial grafts develops slower than at venous ends. Failure or dysfunction of grafts used in coronary artery bypass surgery or peripheral vascular surgery (e.g., aorta-iliac, femoral-femoral, femoral-popliteal, femoral tibial) is well known. Failure of vascular grafts or arterial reconstruction results from luminal narrowing of the vessel or prosthetic conduit, at or away from the anastamotic site, from intraluminal thrombus or a vasculoproliferative response, or from other pathologies, for example, infection of the prosthetic graft.
Neointimal hyperplasia, a manifestation of the vasculoproliferative response, affects the vessel and adjacent graft orifice. The vessel wall thickens and the lumen narrows due to migration and proliferation of smooth muscle cells. The etiology of graft failures may relate to a variety of physical (e.g., shear stress causing hemodynamic disturbance), chemical, or biological stimuli, as well as infection or foreign body rejection, which may explain why fistulae that do not involve a foreign body (e.g., PTFE) remain patent longer than vascular access grafts that involve interposition of a PTFE graft. As the stenosis in the graft becomes progressively more severe, the graft becomes dysfunctional and access for medical procedures suboptimal. Left untreated, stenosis eventually leads to occlusion and graft failure.
The venous ends of grafts are prone to narrowing for multiple reasons. This location is uniquely exposed to arterial pressures and arterial flow rates, dissipation of acoustic or vibratory energy in the vessel wall and surrounding tissue, repeated puncture of the graft, and infusion of processed blood. In addition, in the hemodialysis example, the venous end of the graft may be bathed in mitogens released during passage of the blood through the dialysis tubing or during activation of platelets at the site of needle puncture.
Tissue samples collected from the graft-vein anastomosis site of stenotic PTFE grafts during surgical revision show significant narrowing of the lumen and are characterized by the presence of smooth muscle cells, accumulation of extracellular matrix, angiogenesis within the neointima and adventitia, and presence of an active macrophage cell layer lining the PTFE graft material. A large variety of cytokines and cell growth stimulating factors like platelet-derived growth factor (PDGF), basic fibroblast growth factor (bFGF), and vascular endothelial growth factor (VEGF) are expressed by smooth muscle cells or myofibroblasts within the venous neointima, macrophages lining both sides of the PTFE graft, and vessels within the neointima and adventitia. Macrophages, specific cytokines (PDGF, bFGF, and VEGF), and angiogenesis within the neointima and adventitia have been suggested as likely contributing to the pathogenesis of venous neointimal hyperplasia.
In the hemodialysis example, venous neointimal hyperplasia characterized by stenosis and subsequent thrombosis accounts for the overwhelming majority of pathology resulting in PTFE dialysis graft failure, which prevents hemodialysis, leading to renal failure, clinical deterioration, and death. Vascular access dysfunction is the most important cause of morbidity and hospitalization in the hemodialysis population. Despite the magnitude of the problem and associated costs, however, no effective therapies currently exist for the prevention or treatment of venous neointimal hyperplasia in PTFE dialysis grafts.
Once stenosis has occurred, the treatment consists of further vascular reconstruction. One current method of treatment involves reduction or obliteration of the narrowing and restoration of bloodflow through the graft by non-surgical, percutaneous catheter-based treatments such as balloon angioplasty. This procedure involves deploying a balloon catheter at the site of the blockage and inflating the balloon to increase the minimum luminal diameter of the vessel by compressing the material causing the restriction against the interior of the vessel wall. Depending upon the length and severity of the restriction, the procedure may be repeated several times by inflating and deflating the balloon. When completed, the balloon catheter is withdrawn from the system.
Although balloon angioplasty can be used as a “stand alone” procedure, it is frequently accompanied by deployment of a stent. A stent is an expandable scaffolding or support device that is placed within the vasculature to prevent mechanical recoil and to reduce the chance of renarrowing, or restenosis, at the site of the original restriction. Stents are either “balloon-expandable” or “self-expanding” and when deployed endovascularly, abut against the inner vessel wall. Whether or not a stent is placed, this form of treatment has a high risk of failure, i.e., a high risk of restenosis at the treatment site. Unless stenosis can be effectively and permanently treated, graft failure tends to follow.
In the event of graft failure, the patient must undergo an endovascular procedure, i.e., a non-surgical, catheter-based percutaneous procedure or repeat vascular surgery such as thrombectomy to “declot” the graft or to place another vascular access graft or a shunt at a different site, unless the patient receives a kidney transplant. Given the obvious problems of repeat surgeries and the limited availability of transplants, treatment that is both effective and durable in preventing and treating stenosis is needed.
The vast majority of current approaches for treating the vasculoproliferative response believed to be the pathophysiological basis of stenosis and restenosis is based on treating from within the vascular or graft lumen. One current approach utilizes drug-coated or drug-impregnated stents that are deployed within the lumen of the vessel. Examples of drugs used to coat stents include rapamycin (sirolimus or Rapamune®) commercially available from Wyeth (Collegeville, Pa.) and paclitaxel (Taxol®) commercially available from Bristol-Myers Squibb Co. (New York, N.Y.). In this stent-based approach, rapamycin or paclitaxel gradually elutes from the stent and diffuses into the vessel wall from the intima, the innermost layer of the vessel wall, to the adventitia, the outermost layer of the vessel wall. Studies have shown that rapamycin and paclitaxel tend to inhibit smooth muscle cell proliferation.
Delivery of drugs from the perivascular or extravascular space through the vascular wall, by utilizing a synthetic matrix material (ethylene-vinyl acetate copolymer) together with an anticoagulant that also has antiproliferative properties, e.g., heparin, has been suggested. However, this approach has two disadvantages. Heparin is soluble and rapidly disappears from the vascular wall, and ethylene-vinyl acetate copolymer is not biodegradable, potentially raising concerns about long term effects in vivo.
To effectively deliver a therapeutic agent locally using a matrix material-based system, the matrix material should preferably have certain characteristics. The matrix material should permit the loading of adequate quantity of the therapeutic agent. The matrix material should elute the therapeutic agent at an appropriate, well-defined rate. The matrix material should preferably be implantable and biodegradable, so as to not require physical removal of the matrix material from the recipient's tissue following drug delivery and to obviate concerns about long term effects of the residual matrix.
Furthermore, the matrix material and its biodegradation products should not provoke a significant inflammatory or proliferative tissue response and should not alter or interfere with the recipient's natural defense systems or healing. The device comprising the matrix material and the therapeutic agent should be flexible enough to mould to the contours of the vasculature. The device should also be amenable to being fixed in place, such that it does not migrate to an unintended location.
Polymer matrix materials used for drug delivery within the context of implantable devices can be either natural or synthetic. Examples include but are not limited to polymers composed of chemical substances like polyglycolic acid, polyhydroxybutyrate, ethylene-vinyl acetate, or natural polymers like collagen and fibrin, or polysaccharides such as chitosan. Matrix materials with poor mechanical characteristics, potential immunogenicity, toxic degradation products, inflammatory properties, or a tendency to induce a proliferative response would be inappropriate.
A well-known biocompatible, biodegradable, resorbable matrix material for drug delivery is collagen. The use of collagen as a material for fabrication of biodegradable medical devices has undergone serious scrutiny (U.S. Pat. Nos. 6,323,184; 6,206,931; 4,164,559; 4,409,332; 6,162,247). One current approach using collagen involves delivery of pharmaceutical agents, including antibiotics and physiologically active proteins and peptides such as growth factors. Effective delivery of any therapeutic agent should also preferably not interfere with the natural healing process.